Project Summary Tumors survive cancer therapy in part by blocking the entrance and permeation of drugs into the cancer. We have developed a conjugatable therapeutic, ?JOC-x?, that selectively opens up tumor tight junctions, which dramatically enhances penetration. This results in markedly increased concentrations of cancer drugs in the tumor. JOC-x may allow doctors to treat patients with cancer drugs at increased doses, which directly correlates with enhanced therapeutic effects. At the same time, it could reduce or eliminate the side effects of cancer therapy and address one of the major needs of the current state-of-the-art: Developing therapies that are both more effective and less toxic. Importantly, JOC-x can be used to improve clinical outcomes with cancer drugs that are already on the market as well as the next generation of cancer drugs. The goal of this proposal is to develop and test a JOC-x conjugate formed by linking the tumor- targeting tight junction opener with a chemotherapeutic agent through a polymeric backbone. The targeting and enhancing construct (1) Will be targeted to tumors (2) Will open the tumor microenvironment (3) Will therefore allow for dramatic levels of drug accumulation (4) Will result in increased killing of tumor cells and improved clinical efficacy We will do this research in two straightforward steps: we will first produce and characterize JOC-x conjugates and then we will test the conjugates for enhanced therapeutic efficacy in animal models of ovarian cancer. If we are successful, we will further move this new type of therapy towards clinical testing in humans.